Cell proliferation requires the transfer of mevalonate pathway intermediates to a group of proteins, small G-proteins and the nuclear lamins among others. Agents targeted to the inhibition of the transfer process (farnesylation, geranylgeranylation), e.g., farnesyl mimetics and perillyl alcohol, have potential value as chemotherapeutic agents. Agents that block the synthesis of the mevalonate pathway intermediates, e.g., inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase (statins) and mevalonate kinase (sodium phenylacetate) also have therapeutic potential. The statins competitively inhibit HMG CoA reductase activity. Diverse end products of plant mevalonate metabolism (pure and mixed isoprenoids) suppress HMG CoA reductase activity (Elson, 1995; Elson and Qureshi, 1995; Elson and Yu, 1994).
The endogenous isoprenoids, the monoterpene and sesquiterpene alcohols geraniol and farnesol, also suppress reductase activity. Geraniol attenuates the HMG CoA reductase mRNA translational efficiency and decreases reductase mRNA (Elson, et al., 1998). Farnesol attenuates reductase mRNA translational efficiency and signals the proteolytic degradation of HMG CoA reductase (Correll, et al., 1994). These isoprenoids accumulate in mammalian cells only in the presence of excess mevalonate. These prenyl alcohols have relatively short biological half-lifes as they are rapidly converted to .alpha.,.omega.-prenyl dicarboxylic acids by cytosolic dehydrogenase and microsomal monooxygenase activities which sequentially catalyze the formation of prenyl aldehydes, .alpha.-prenoic acids, .omega.- and .omega.-3-hydroxy-.alpha.-prenoic acids and .alpha.,.omega.-prenyl dicarboxylic acids (Christophe and Popjak, 1961; Gonzales-Pacanowska, et al., 1988; Austin, et al., 1988; Keung, 1991; Giron, et al., 1993).
Pentobarbital, an inducer of the microsomal P450 monooxygenase activity that catalyzes the formation of .omega.- and .omega.-3 hydroxy-.alpha.-prenoic acids, totally reverses the isoprenoid-mediated suppression of HMG CoA reductase activity (Yu, et al., 1994). These inducible activities decrease the half-life of the endogenous isoprenoids (geraniol and farnesol) that down-regulate reductase activity.